Project Summary/Abstract Vertebrate sight and human visual health depend upon the dynamic architecture of rod and cone photore- ceptor outer segments (OSs). A broad variety of sight-robbing diseases is associated with defects in OS architecture; however, neither the underlying disease etiology, nor the fundamental biology of the receptor cells is well understood. Although speculative models for OS morphogenesis and scaffolding have been proposed, the molecular mechanisms responsible for organizing this organelle are not known. To address this knowledge gap, the long-term goal of this research is to define OS membrane architecture and renewal in sufficient detail to explain how defects in this organelle generate retinal disease. The current goal is to determine how peripherin-2/rds (P/rds) functions as an organizer for OS membranes. This integral mem- brane protein acts in an essential, though mechanistically uncertain (and differential) fashion to support OS architecture for both rods and cones. Inherited defects in P/rds cause a broad range of progressive dis- eases, including retinitis pigmentosa and macular degenerations. The first Aim of this study will test the novel hypothesis that P/rds can function in trans to shape and tether OS disk rims via a hydrophobic inser- tion mechanism. The second Aim will test the hypothesis that that P/rds self-assembly and/or heterotypic interactions can regulate activity for membrane curvature and/or tethering. The third Aim will test the hy- pothesis that pathogenic mutations impair P/rds activity for membrane curvature generation and/or tether- ing. Completion of these aims would establish a new model for P/rds function and OS membrane organiza- tion. The work would also make a positive impact on the field by providing a new conceptual framework for rationalizing phenotype-genotype relationships for inherited defects in human P/rds and potentially manag- ing progressive retinal degenerations that result from primary pathologies in OS structure.